The mechanism of morphine's analgesic action has been hypothesized to involve, at least in part, binding to receptors in the periaqueductal gray (PAG) of the reticular formation. The depression of PAG cells thereby induced serves to disinhibit the serotonergic raphe nuclei, which in turn exert analgesis action through their projections to higher centers and to the spinal cord. A direct action of morphine on the spinal cord has also been demonstrated. It is not known, however, if the PAG/raphe system and spinal cord are universally involved in the action of all centrally acting analgesic drugs. Demonstrations that analgesia produced by various non-pharmacological means (stress, vaginal probing, intracranial stimulation at non-PAG sites) does not involve the PAG/raphe system indicate the presence of alternate analgesic substrates which would be available for activation by pharmacological agents. The proposed study seeks to systematically determine the involvement of the PAG/raphe system and of the spinal cord in the action of centrally acting analgesic drugs of the following groups: general anesthetics, muscle relaxants, cannabinoids, cyclic nucleotides, and the opioids acting at the k receptor. The methods will include assessment of analgesia induced by a given agent following: (1) lesion of individual raphe nuclei; (2) pharmacological manipulation of serotonergic activity; and (3) local application of drugs to the PAG, to other brain sites, and to the spinal cord. These studies will add significantly to our knowledge of analgesic drug mechanisms and of the physiological basis of pain perception. In addition, this detailed information will inform the search for new analgesic drugs which operate through CNS pathways other than those activated by morphine.